(a) Field of the Invention
This invention relates to novel 7-carboxymethoxyphenylacetamido-3-cephem derivatives represented by the formula: ##STR3## wherein R.sub.1 means hydroxy, C.sub.1 -C.sub.4 alkanoyloxy or C.sub.1 -C.sub.4 alkoxycarbonyloxy, R.sub.2 is hydrogen or methoxy, R.sub.3 denotes C.sub.1 -C.sub.4 alkanoyloxy, substituted or unsubstituted nitrogen-containing hetrocyclic-thio or substituted or unsubstituted pyridinium with a proviso that, when R.sub.3 denotes the substituted or unsubstituted pyridinium, R.sub.3 forms an intramolecular salt with the carboxy at the 4-position of the cephem nucleus, and A is a group of the following formula: ##STR4## in which R.sub.4 and R.sub.5 are individually hydrogen or C.sub.1 -C.sub.4 alkyl, or a pharmaceutically acceptable salt thereof, processes for the preparation thereof, and antibacterial preparations containing the same.
In the above formula (I), acetoxy, propionyloxy, butyryloxy, isobutyryloxy, etc. may be mentioned as exemplary C.sub.1 -C.sub.4 alkanoyloxy groups represented by R.sub.1 and R.sub.3 while methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like many be mentioned as illustrative C.sub.1 -C.sub.4 alkyl groups represented by R.sub.4 and R.sub.5. As exemplary C.sub.1 -C.sub.4 alkoxycarbonyloxy groups represented by R.sub.1, may be mentioned ethoxycarbonyloxy and methoxycarbonyloxy groups.
The term "substituted or unsubstituted nitrogen-containing heterocyclic-thio" represented by R.sub.3 in the formula (I) means substituted or unsubstituted heterocyclic-thio containing one or more nitrogen atoms as hetero atom or atoms of the heterocyclic nucleus. The group may be a mono- or polycyclic-thio group, and may optionally contain one or more sulfur and/or oxygen atoms in the heterocyclic nucleus, in addition to the nitrogen atom or atoms. Illustrative nitrogen-containing heterocyclic nuclei of the heterocyclic-thio may include such as pyrrolyl, pyridyl and the N-oxide thereof, imidazolyl, parazolyl, pyrimidinyl, pyridazinyl, tetrazolo[4,5-b]pyridazinyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,5,6-tetrahydro-5,6-dioxo-as-triazinyl, 1H-tetrazolyl, 2H-tetrazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, morpholino, benzothiazolyl, benzoxazolyl, etc. These heterocyclic nuclei and the pyridinium group may each contain one or more substituents selected from C.sub.1 -C.sub.4 alkyl groups such as methyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like; carboxyalkyl groups such as carboxymethyl, carboxyethyl and the like; sulfoalkyl groups such as sulfomethyl, sulfoethyl, etc.; amino groups; N,N-dialkylaminoalkyl groups such as N,N-dimethylaminomethyl, N,N-diethylaminoethyl, N,N-dimethylaminoethyl; carbamoyl groups; N-alkylcarbamoyl groups such as N-ethylcarbamoyl, N-methylcarbamoyl, etc.; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and the like; carboxyl group; sulfo group; cyano group; N-hydroxycarbamoyl group; N-hydroxycarbamoylalkyl groups such as N-hydroxycarbamoyl methyl, N-hydroxycarbamoylethyl and the like; carbamoylalkyl groups such as carbamoylethyl, carbamoylmethyl, etc.; N,N-dialkylcarbamoyl groups such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.; N-hydroxy-N-alkylcarbamoyl groups such as N-hydroxy-N-methylcarbamoyl, N-hydroxy-N-ethylcarbamoyl and the like; hydroxyl group; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl and the like; and alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, methoxycarbonylethyl and the like.
As specific groups represented by R.sub.3, may for example be mentioned acetoxy, (1-methyl-5-tetrazolyl)thio, (1-carboxymethyl-5-tetrazolyl)thio, [5-methyl-2-(1,3,4-thiadiazolyl)]thio, [1-(2-N,N-dimethylaminoethyl)-5-tetrazolyl]thio, [5-carboxymethyl-2-(1,3,4-thiadiazolyl]thio, [5-carboxymethyl-2-(1,3,4-oxadiazolyl)]thio, pyridinium, 4-carbamoylpyridinium, 4-(2-sulfoethyl)pyridinium, 3-carboxymethylpyridinium, 3-carboxypyridinium, 4-carboxypyridinium, 4-cyanopyridinium, 4-sulfopyridinium, 3-carbamoylpyridinium, 4-N-hydroxycarbamoylpyridinium, 4-N-hydroxy-N-methylcarbamoylpyridinium and 4-(2-N,N-dimethylaminoethyl)pyridinium.
Furthermore, the following groups may for example be mentioned as specific groups represented by A in the formula (I): ##STR5##
As the pharmaceutically acceptable salts of the compounds of the general formula (I), may be mentioned those commonly employed for cephalosporin derivatives. They may for example be the sodium, potassium, calcium, ammonium, triethylamine, dicyclohexylamine and procaine salts.
(b) Description of the Prior Art
7-Phenylacetamido-3-cephem derivatives containing benzopyran or quinoline have been proposed in recent years, as disclosed in Japanese Patent Application Laid-open Nos. 136292/1980, 5487/1981, 73087/1981, 122384/1981, 18689/1982, 165389/1982, 165390/1981, the corresponding U.S. Pat. Nos. 4285939, 4285941, 4285940, 4344944, 4344944, 4468394, 4468394, respectively, etc. These compounds have strong antibacterial activities against Gram-negative bacteria, notably, Pseud. aeruginosa, Kleb. pneumoniae, Ser. marcescens and the like and are very effective against a variety of infectious diseases. However, each of these compounds is primarily excreted into bile when administered in animals and its excretion rate into urine does not reach even 1% when administered in mice by the subcutaneous route. These compounds are still effective, even at such a low excretion rate into urine as mentioned above, against infections of the urinary tract owing to their very strong antibacterial activities. However, there is a standing demand for the development of 7-phenylacetamido-3-cephem derivatives having higher excretion rates into urine.